Field of the Invention
The invention generally relates to 5-alkylidenethiazolidine-2,4-dione and 3-alkylidene-1,3-dihydro-indol-2-one analogs and their use as selective sphingosine kinase 2 (SphK2) inhibitors in clinical implications. In particular, the invention provides 5-alkylidenethiazolidine-2,4-dione and 3-alkylidene-1,3-dihydro-indol-2-one analogs and derivatives thereof as SphK2 inhibitors and for use in the treatment of cancer.
Background of the Invention
Sphingosine-1-phosphate (S1P), a lipid metabolite, has been recognized and demonstrated as an important signaling mediator for vital cellular and physiological processes, such as cell motility, invasion, proliferation, angiogenesis and apoptosis. S1P is produced from sphingosine by two kinases, namely, sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2). Upon production, S1P is secreted and interacts with a family of G-protein coupled receptors (S1P1-5) on the cell surface to impart a plethora of roles in the regulation of diverse physiological functions such as inflammation, immunity and angiogenesis. Recently, intracellular targets, such as histone deacetylase (HDAC) and TRAF2, have been identified for S1P produced by SphK1 and SphK2, respectively, thus suggesting additional intracellular roles of this sphingolipid metabolite.
S1P and its biosynthetic precursors ceramide and sphingosine are the best characterized bioactive metabolites of sphingolipids. Ceramide and sphingosine have been associated with growth arrest and apoptosis. In contrast, S1P has been demonstrated to play important pro-survival roles. Therefore, the levels of these lipid metabolites need to be tightly controlled and a so called sphingolipid rheostat has been proposed to be crucial in determining cell fate. The regulation of the levels of these metabolites is complex and a number of enzymes have been demonstrated to play important roles, among which the SphKs have emerged as a central player in this complex system. SphKs are the key enzymes that catalyze the production of S1P. To date, two isoenzymes, SphK1 and SphK2 have been identified in human tissues. Although SphK1 and SphK2 share a high degree of homology, they have significant differences in size, tissue distribution, and subcellular localization, thus suggesting their distinct roles in regulation of different physiological functions. For example, SphK1 is mainly localized in the cytosol while SphK2 is present in several intracellular compartments, mainly in the nucleus, endoplasmic reticulum, and mitochondria. Evidence has accumulated that SphK1 promotes cell growth and survival while the function of SphK2 is complex and controversial. Consistent with this notion, numerous studies have shown that SphK1 is frequently up-regulated and overexpressed in tumor tissues compared to normal tissues and SphK1 has been associated with many aspects of cancer progression such as proliferation, migration, invasion and angiogenesis. SphK1/S1P has also been implicated in the pathology of asthma, inflammatory diseases and sepsis. Compared to SphK1, much less is known about SphK2 and the results are contrasting. Initially, SphK2 had been demonstrated to be pro-apoptotic. For example, overexpression of SphK2 suppresses growth and promotes apoptosis. However, it has also been demonstrated that downregulation of SphK2 inhibits the proliferation and migration of tumor cells such as glioblastoma and breast cancer cells. These controversial results strongly suggest developing powerful and selective pharmacological tools for SphK2 to better understand the roles of SphK2 in different pathological conditions. Even though a number of pan-SphK and selective SphK1 inhibitors have been developed and reported, the development of SphK2-selective inhibitors remains limited and SphK2 inhibitors remain scarce, with only a few SphK2 inhibitors having been reported in the literature (e.g. ABC294620, SG-12, R-FTY720-OMe and trans-12). Therefore, there is an urgent need to develop SphK2-selective inhibitors.